References may be made to Journal “Pettit, G. R.; Singh, S. B.; Hamel, E.; Lin, C. M.; Alberts, D. S.; Garcia Kendall, D. Experientia 1989, 45, 209” wherein Combretastatins, a group of antimitotic agents isolated from the bark of the South African willow tree Combretum caffrum Kuntz has attracted considerable interest of medicinal chemists in the design of analogues as novel antitumor agents. Combretastatin A-4 (1) appears to be the most active in the group, and remarkably simple in the chemical structure, while possessing unique dual features anti-tubulin and anti-vascular agent. CA-4 strongly inhibits the polymerization of tubulin by binding to the colchicine site. Because of its simple structure, a large number of CA-4 analogues have been developed and evaluated in SAR studies. Among synthetic small-molecule tubulin inhibitors, replacement of the double bond of with a carbonyl group furnished a benzophenonetype CA-4 analogue named phenstatin. This compound demonstrated interesting efficacy in a variety of tumor models while retaining the characteristics of (1) The 2-aminobenzophenone derivative also strongly inhibited cancer cell growth and tubulin polymerization and caused mitotic arrest, as phenstatin did.
Reference may be made to Journal “Ohsumi, K; Hatanaka, T.; Fujita, K.; Nakagawa, R.; Fukuda, Y.; Nihei, Y.; Suga, Y.; Morinaga, Y.; Akiyama, Y.; Tsuji, T. Bioorg. Med. Chem. Lett. 1998, 8, 3153” wherein many synthetic analogues have been developed following the strategy of design of two-atom bridgehead analogues utilizing 1,2-oriented heterocycles are described. In contrast, a limited number of analogues have been successfully designed following the strategy of three-atom bridgeheads 1,3-oriented with a linear- or heterocycle-linker inserted between the two aryl rings of combretastatins.
Reference may be made to Journal “Edwards, M. L.; Stemerick, D. M.; Sunkara, P. S. J. Med. Chem. 1990, 33, 1948A” wherein a series of chalcones and a large collection of oxazoline and oxadiazoline derivatives are described.
Reference may be made to Journal “Wu-Wong, J. R.; Alder, J. D.; Alder, L.; Burns, D. J.; Han, E. K.; Credo, B.; Tahir, S. K.; Dayton, B. D.; Ewing, P. J.; Chiou, W. J. Cancer Res. 2001, 61, 1486” wherein analogues of A-105972 obtained in the Abbott Laboratories. modifications of the ethylene bridge in this class of compounds with the five member ring like imidazolone type of compounds (4) have led to interesting biological profile, particularly exhibits significant anticancer activity “Cenzo Congiu, Maria Teresa Cocco, Valentina Onnis, Bioorg. Med. Chem. Lett. 2008, 18, 989”
Chemical Structures of Combretstatin (1), A-105972 (2), Chalcones (3), and Imidazolones (4)
Furthermore Chalcones (3) are a class of anticancer agents that have shown promising therapeutic efficacy for the management of human cancers. Chalcones, considered as the precursor of flavonoids and isoflavonoids, are abundant in edible plants.
Chemically they consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon R,â-unsaturated carbonyl system. Licochalcone-A, a chalcone derivative found in the licorice root, has been associated with a wide variety of anticancer effects “Park, E. J.; Park, H. R.; Lee, J. S.; Kim, J. Planta Med. 1998, 64, 464” Chalcones inhibit the proliferation of both established and primary ovarian cancer cells “De Vincenzo, R.; Scambia, G.; Benedetti Panici, P.; Ranelletti, F. O.; Bonanno, G.; Ercoli, A.; Delle Monache, F.; Ferrari, F.; Piantelli, M.; Mancuso, S. Anticancer Drug Des. 1995, 10, 481”. In vivo, chalcones have been demonstrated to be effective as antitumor agents in skin carcinogenesis “Statomi, Y. Int. J. Cancer 1993, 55, 506) and chemopreventive agents in several experimental models (Rui, H. J. Cell. Biochem. 1997, 67, 7”. Recent studies have shown that these chalcones induce apoptosis in variety of cell types, including breast cancers “Claude-Alain, C.; Jean-Chritophe, L.; Patrick, T.; Christelle, P.; Gerard, H.; Albert-Jose, C.; Jean-Luc, D. Anticancer Res. 2001, 21, 3949”
References may be made to an Journal “Cenzo congiu, Maria Teresa Cocco and vValentina onnis, Bioorganic and medicinal chemistry letters, 18, 2008, 989-993” wherein a series of new 1,4-diarylimidazol-2(3H)-one derivatives and their 2-thione analogues has been prepared and evaluated in vitro for antitumor activity against the NCI human cancer cell panel. Compounds bearing a 3,4,5-trimethoxyphenyl ring linked to either N-1 or C-4 position of the imidazole core demonstrated an interesting profile of cytotoxicity with preferential activity against leukemic cell lines. Compound 13 exhibited a potent antitumor activity against MOLT-4 (GI50=20 nM) and SR (GI50=32 nM) cell lines.
References may be made to an article published in bioorganic and medical chemistry letters 18 (2008) 989-993 “Design, synthesis, and in vitro antitumor activity of new 1,4-diarylimidazole-2-ones and their 2-thione analogues” wherein a series of new 1,4-diarylimidazol-2(3H)-one derivatives and their 2-thione analogues has been prepared and evaluated in vitro for antitumor activity against the NCI human cancer cell panel. Compounds bearing a 3,4,5-trimethoxyphenyl ring linked to either N-1 or C-4 position of the imidazole core demonstrated an interesting profile of cytotoxicity with preferential activity against leukemia cell lines.
Present invention provides improved anticancer activity against fifty three human cancer cell lines.